This proposal provides a mentored research and career development program for the establishment of an independent academic research career focused on the elucidation of basic mechanisms of neural aging and neurodegeneration. The candidate is currently an Instructor in the Division of Molecular Biology and Department of Medicine at Children's Hospital and Harvard Medical School. As proposed, the candidate will conduct research under the mentorship and guidance of Dr. Frederick Alt, Dr. Li-Huei Tsai, and Dr. Bruce Yankner, who are foremost experts in mouse genetics, DNA repair, neurobiology, and age-related neurodegenerative disorders, respectively. During the latter portion of the award, the candidate should be well positioned to successfully seek independent research project grant (RO1) support for studies in the neurobiology of aging and neurodegeneration that develop from his mentored research. The candidate's preliminary work has shown that Sirtuin 6 (Sirt6) is a major neural histone deacetylase with implications for neural functioning. In the proposed research plan, the candidate will investigate the role of Sirt6 in maintenance of neuronal integrit and cognitive function across the lifespan (Aim 1), and elucidate a potential role of Sirt6 in Alzheimer's disease (Aim 2) by using novel mutant mouse lines, and a variety of techniques including histopathology, electrophysiology, behavioral analysis, and molecular biology approaches. A personalized career development plan that takes full advantage of the expertise and resources of the exceptionally strong mentoring team and institutional environment is proposed for the candidate to allow him to focus his scholarship on neural aging and neurodegeneration, to develop expertise in the neuropathology and basic neurobiology of aging and neurodegenerative disorders, and to train him in the use of advanced neurobiological and neurobehavioral methods. The institution is fully committed to providing the necessary resources and training to help the candidate establish his independent career. The increasing number of people affected by age-related dementia, mainly in the form of Alzheimer's disease, is one of the greatest public health challenges of the 21st century but no treatments are available. The collective results from the proposed research will provide insights into processes related to normal brain physiology, aging and neurodegeneration, as well as deepen the understanding of sirtuin biology. Ultimately, the proposed studies may provide a foundation for the identification of new therapeutic targets and preventive approaches for Alzheimer's disease and other age-related neurodegenerative disorders. PUBLIC HEALTH RELEVANCE: Age-related dementia, mostly in the form of Alzheimer's disease, is already one of the greatest public health challenges in the world and the number of affected people is expected to double in the next 20 years. Despite the devastating implications, no treatments are available. The identification of molecular pathways protecting brain function during normal aging and in the context of neurodegenerative disorders will contribute to our understanding of such diseases and may ultimately be critical for their prevention and treatment.